PROCEDE DE PREPARATION DE DERIVES D'ACRYLATE DE CYANOPHENOXY-PYRIMIDINYLOXYPHENYLE SUBSTITUE

PROCESS FOR THE PREPARATION OF SUBSTITUTED CYANOPHENOXY-PYRIMIDINYLOXY-PHENYL ACRYLATE DERIVATIVES

Abrégé français

La présente invention concerne un procédé de réaction entre un dérivé de phénol et un substrat aromatique dans des conditions formant un phénolate comprenant les étapes suivantes : (a) la réaction d'un dérivé phénolique avec une base dans un solvant organique polaire pour obtenir un sel phénolate, l'eau étant éliminée du mélange réactionnel au cours de la réaction, (b) l'addition du substrat aromatique au mélange réactionnel obtenu dans l'étape (a), (c) le chauffage du milieu réactionnel de l'étape (b) à une température située dans la plage de 80 à 130ºC, de préférence, 90 à 100ºC pendant 2 à 7 heures pour obtenir un substrat aromatique à substitution phénoxy, (d) l'élimination du solvant du mélange de l'étape (c) et l'isolement et la purification additionnels du substrat aromatique à substitution phénoxy. Eventuellement, l'élimination de l'eau au cours de l'étape (a) est réalisée conjointement avec l'élimination partielle du solvant organique.

Abrégé anglais

The present invention provides a process for reacting between a phenol derivative and an aromatic substrate under phenolate forming conditions comprising the following steps: (a) reacting a phenol derivative with a base in a polar organic solvent to obtain a phenolate salt, wherein water is removed from the reaction mixture during the reaction. (b) adding the aromatic substrate to the reaction mixture obtained in step (a), (c) heating the reaction mixture of step (b) to a temperature in the range of 80° to 1300C, preferebly, 90- 1000C for 2 to 7 hours to obtain a phenoxy substituted aromatic substrate, (d) removing the solvent from the mixture of step (c) and further isolating and purifying the phenoxy substituted aromatic substrate. Optionally, the removal of water during step (a) is in conjunction with partial removal of the organic solvent.

Revendications

Claims
1. A process for reacting between a phenol derivative and an aromatic
substrate under
phenolate forming conditions comprising the following steps:
a) reacting a phenol derivative with a base in a polar organic solvent to
obtain a
phenolate salt, wherein water is removed from the reaction mixture during the
reaction,
b) adding the aromatic substrate to the reaction mixture obtained in step (a),
c) heating the reaction mixture of step (b) to a temperature in the range of
80° to
130°C,preferebly, 90-100°C for 2 to 7 hours to obtain a phenoxy
substituted
aromatic substrate,
d) removing the solvent from the mixture of step (c) and further isolating and
purifying the phenoxy substituted aromatic substrate.
2. A process according to claim 1, wherein the removal of water during step
(a) is in
conjunction with partial removal of the organic solvent..
3. A process according to claim 1, wherein the mole ratio between said phenol
derivative.
and base is 1:1 to 1:1.5, preferably 1:1.125 to 1:1.15..
4. A process according to claims 1 to 3, wherein the time required for step
(a) to obtain
conversion to a phenolate salt is 30 to 120 minutes at a temperature between
60°C to
80°C, while partially removing solvent with water from the reaction
mixture by vacuum
distillation.
5. A process according to claims 1 to 4, wherein the phenol derivative may be
phenol,
mono-substituted phenol or poly-substituted phenol, more preferably,
cyanophenol
derivatives, including 2-cyanophenol and 4-cyanophenol.
6. A process according to claims 1 to 5, wherein said base is selected from
among
hydroxide and carbonate bases, including metal hydroxides, alkali metal
hydroxides,
metal carbonates and alkali metal carbonates, preferably, sodium hydroxide,
potassium
hydroxide, sodium or potassium carbonate.
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7. A process according to claim 1, wherein preferred polar organic solvents
are dimethyl
formamide (DMF), dimethyl acetamide (DMAA) and dimethyl sulphoxide (DMSO)
wherein, preferably the range of the reagent/solvent ratio is 0.1mole/150ml-
0.1mole/350ml.
8. A process according to claim 1, wherein said aromatic substrate may be
added in step
(b) together with a polar organic solvent.
9. A process according to claim 1, wherein the aromatic substrate is added in
an amount
such that the mole ratio between the phenol derivative and aromatic substrate
is between
1: 0.8 and 1:1, preferably 1:1.
10. A process according to claim 1, wherein the aromatic substrate is selected
from
among mono and poly-substituted pyridine, pyrimidine and phenyl groups,
preferably, at
least mono-halo substituted and more preferably chloro-pyrimidine derivatives.
11. A process according to claim 1, wherein heating the reaction mixture of
step (b) to a
temperature in the range of 80° to 130°C, preferably about 100
°C for 2 to 7 hours,
preferably about 5 hours to obtain a phenoxy substituted aromatic substrate,
12. A process according to any of claims 1 to 11 for the preparation of methyl
(E)-2-{2-
[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (azoxystrobin)
comprising of the following steps:
a) reacting 2-cyanophenol with an alkali metal hydroxide or carbonate, in a
polar
organic solvent, at a temperature between 60°C to 80°C ,
preferably between
60°C to 70°C for about 1 hour, while removing the water which is
formed
during the reaction via distillation with the solvent under reduced pressure,
b) adding the aromatic substrate which is (E)-Methyl 2-[2-(6-chlorpyridimin-4-
yloxy)phenyl]-3-methoxypropenoate, Compound of formula (I) to the reaction
mixture obtained in step (a), optionally, Compound (I) is added to the
reaction
mixture as a solution in DMAA;
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<IMG>
c) heating the reaction mixture of step (b) to a temperature in the range of
80° to
130°C, preferably 90°C to 100°C for 2 to 7 hours,
preferably 4 to 6 hours to
obtain azoxystrobin,
d) removing the solvent from the mixture of step (c) by distillation under
reduced
pressure; and further washing and extracting the reaction mixture with a non-
polar organic solvent, and adding water to obtain an organic and aqueous
phase, thereafter discarding the aqueous phase and crystallizing the
azoxystrobin from the organic phase by cooling the organic solvent, filtering
the precipitated solid and rinsing thereafter with an alcohol, preferably
methanol to obtain azoxystrobin with purity of 98%-99%.
13. A process according to claim 12, wherein said base is sodium hydroxide,
potassium
hydroxide, sodium carbonate or potassium ccarbonate.
14. A process according to claims 12 to 13 wherein said polar organic solvent
is selected
from a group comprising DMF, DMAA and DMSO, more preferably DMAA.
15. A process according to claims 12 to 14 wherein removing the water which is
formed
during the reaction of step (a) is via distillation with the solvent under
reduced pressure,
preferably about 20-30mbar., wherein the mole ratio between 2-cyanophenol and
base is
between 1:1 and 1:1.5.
16. A process according to claims 12 to 15, wherein said non-polar organic
solvent of
step (d) is selected from a group comprising toluene, xylene, at least C4
acetate esters,
preferably, butylacetate.
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17. A process according to claim 12 comprising;
a) reacting 2-cyanophenol with sodium hydroxide in DMAA and DMSO, more
preferably DMAA, at a temperature between 60°C to 80°C for about
1 hour,
while removing the water which is formed during the reaction via distillation
with the solvent under reduced pressure of about 20-30mbar, wherein the
mole ratio between 2-cyanophenol and sodium hydroxide is between 1:1 and
1:1.5;
b) adding the aromatic substrate which is (E)-Methyl 2-[2-(6-chlorpyridimin-4-
yloxy)phenyl]-3-methoxypropenoate, Compound of formula (I) to the reaction
mixture obtained in step (a), wherein Compound (I) is added to the reaction
mixture as a solution in DMAA.
<IMG>
c) heating the reaction mixture of step (b) to a temperature in the range of
90°C
to 100°C for 4 to 6 hours to obtain azoxystrobin,
d) removing the solvent from the mixture of step (c) by distillation under
reduced
pressure; and further washing and extracting the reaction mixture with
butylacetate and adding water to obtain an organic and aqueous phase,
thereafter discarding the aqueous phase and crystallizing the azoxystrobin
from the organic phase by cooling the organic solvent, filtering the
precipitated solid and rinsing thereafter with methanol to obtain azoxystrobin
with purity of 98%-99%.
18. A process as herein exemplified and described
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Description

CA 02671414 2009-06-02
WO 2008/075341 PCT/IL2007/001551
Process for the Preparation of Substituted Cyanophenozy-Pyrimidinylozy-phenyl
Acrylate Derivatives
Field of the Invention
The present invention relates to the field of chemical synthesis, particularly
to
improved processes for synthesizing substituted cyanophenoxy-pyrimidinyloxy-
phenyl
acrylate derivatives.
Background of the Invention
In the field of industrial chemical synthesis, the improvement of the yield
and
selectivity of chemical processes bears considerable impact on the industry.
Particularly,
the focus in said improvements is on lowering costs, simplifying unit
operations and
environmental considerations. These three factors are particularly important
in the field
of agrochemicals where the volume of chemicals is large and the marginal
profit is
relatively small.
Of the many agrochemical compounds which are synthesized by multi-stage
synthesis, methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-
methoxyacrylate (chemical common name: azoxystrobin), particularly drew the
attention
of the present inventors. Azoxystrobin, disclosed in U.S. Patent No.
5,395,837, is a plant
protection fungicide with protectant, curative, eradicant, translaminar and
systemic
properties. The preparation of azoxystrobin as described in Example 3 of U.S.
5,395,837
involves an aromatic substitution reaction between 2-cyanophenol and (E)-
Methyl 2-[2-
(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate also known as (E)-Methyl
-2-
[2-(6-chloropyrimidin-4-yloxy)-phenyl]-3-methoxyacrylate, at temperatures at
95 to
100 C in DMF in the presence of stoichiometric amounts of potassium carbonate
and a
catalytic amount of copper(I) chloride. The reported yield of azoxystrobin is
65%
wherein the product was found to have a melting point of 110 C -111 C,
indicating a final
product of relatively low purity, which subsequently required further
purification. It has
been suggested that reactions of 2-cyanophenol or other isomers of cyanophenol
or
phenols in general under conditions of temperatures of about 90 C and above,
in the
presence of basic reagents which can promote the formation of phenolate salts,
may cause
polymerization and the formation of tars. This clearly is a highly undesirable
side effect.
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Accordingly there is an ongoing and long felt need for a process for aromatic
substitution reactions in the presence phenols with improved yield and
selectivity.
Thus, it is the objective of the present invention to provide a process for
reacting
phenols under basic conditions in which the yield and selectivity is improved.
Other objectives of the invention shall become apparent as the description
proceeds.
Summary of the Invention
The present invention provides a process for reacting between a phenol
derivative
and an aromatic substrate under phenolate forming conditions comprising the
following
steps:
a) reacting a phenol derivative with a base in a polar organic solvent to
obtain a
phenolate salt, wherein water is removed from the reaction mixture during the
reaction.
b) adding the aromatic substrate to the reaction mixture obtained in step (a),
c) heating the reaction mixture of step (b) to a temperature in the range of
80 to
130 C,preferebly, 90-100 C for 2 to 7 hours to obtain a phenoxy substituted
aromatic substrate,
d) removing the solvent from the mixture of step (c) and further isolating and
purifying the phenoxy substituted aromatic substrate.
Optionally, the removal of water during step (a) is in conjunction with
partial removal of
the organic solvent.
Detailed Description of the Invention
The following description is illustrative of embodiments of the invention. The
following description is not to be construed as limiting, it being understood
that the
skilled person may carry out many obvious variations to the invention.
Throughout the
specification the terms "phenols" and "phenol derivative" include phenol and
mono and
poly-substituted phenols, including 2-cyanophenol and other cyanophenol
isomers.
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The present invention provides a process for reacting between a phenol
derivative
and an aromatic substrate under phenolate forming conditions wherein the
formation of
polymeric by-products and tars are minimized. In minimizing said by-products
and tars
formation, the present process provides improved yields together with
facilitation of
product separation and purification. The present process provides yields of
90% and
greater, wherein said yield is calculated on the basis of the aromatic
substrate. It has been
surprisingly found that generating the phenolate salt separately and
subsequently reacting
said phenolate salt with the aromatic substrate, prevents the formation of
undesirable by-
products and tars.
The present process comprises the following steps:
a) reacting a phenol derivative with a base in a polar organic solvent to
obtain a
phenolate salt,, wherein water is removed from the reaction mixture during the
reaction.
Step (a) is conducted wherein the mole ratio between said phenol derivative
and
base is preferably between 1:1 to 1:1.5, preferably 1:1.125 to 1:1.15. The
time required
for step (a) to obtain conversion to a phenolate salt is 30 to 120 minutes at
a temperature
between 60 C to 80 C, while partially removing solvent with water from the
reaction
mixture by vacuum distillation.
According to a preferred embodiment of the present invention said phenol
derivative may be phenol, mono-substituted phenol or poly-substituted phenol,
more
preferably, cyanophenol derivatives, including 2-cyanophenol and 4-
cyanophenol.
Said base may be selected from among hydroxide and carbonate bases, including
but not limited to metal hydroxides, alkali metal hydroxides, metal carbonates
and alkali
metal carbonates preferably, sodium hydroxide or potassium hydroxide.
Non-limiting examples of preferred polar organic solvents are dimethyl
formamide (DMF), dimethyl acetamide (DMAA) and dimethyl sulphoxide (DMSO)
wherein, preferably the range of the reagent/solvent ratio is 0.lmole/150m1-
0.1 mole/350m1.
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According to a specific embodiment of the invention, the phenolate salt is
formed
via partial removal of solvent with water under reduced pressure conditions.
b) adding the aromatic substrate to the reaction mixture obtained in step (a).
According to a particular embodiment of the invention said aromatic substrate
may be added together with a polar organic solvent selected from the afore-
mentioned
group of solvents. The aromatic substrate is added in an amount such that the
mole ratio
between the phenol derivative and aromatic substrate is between 1: 0.8 and 1:1
In yet a further preferred embodiment of the invention, the aromatic substrate
is
selected from among mono and poly-substituted pyridine, pyrimidine and phenyl
groups.
Preferably, at least mono-halo substituted and more preferably chloro-
pyrimidine
derivatives.
c) heating the reaction mixture of step (b) to a temperature in the range of
800 to
130 C, preferably about 100 C for 2 to 7 hours, preferably about 5 hours to
obtain a phenoxy substituted aromatic substrate,
d) removing the solvent from the mixture of step (c) and further isolating and
purifying the phenoxy substituted aromatic substrate.
The operations of step (d) can be carried out according to methods known to
the skilled
artisan. Said methods include; solvent removal by distillation wherein said
distillation
may be carried out under reduced pressure conditions, separation and
purification by
washing, extraction and crystallization.
According to a specific preferred embodiment of the present invention, there
is provided
a process for the preparation of methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-
4-
yloxy]phenyl}-3-methoxyacrylate (azoxystrobin) comprising of the following
steps:
a) reacting 2-cyanophenol with an alkali metal hydroxide or carbonate,
preferably sodium hydroxide in a polar organic solvent preferably selected
from among DMF, DMAA and DMSO, more preferably DMAA, at a
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temperature between 60 C to 80 C , preferably between 60 C to 70 C for
about 1 hour, while removing the water which is formed during the reaction
via distillation with the solvent under reduced pressure, preferably about 20-
30mbar. The mole ratio between 2-cyanophenol and alkali metal hydroxide is
between 1:1 and 1:1.5.
b) adding the aromatic substrate which is (E)-Methyl 2-[2-(6-chloropyridimin-4-
yloxy)phenyl]-3-methoxypropenoate (Compound of formula (I) to the reaction
mixture obtained in step (a). Optionally. Compound (I) is added to the
reaction mixture as a solution in DMAA.
N^N
\ I I /
C1
Me
OOMe
(I)
c) heating the reaction mixture of step (b) to a temperature in the range of
80 to
130 C, preferably 90 C to 100 C for 2 to 7 hours, preferably 4 to 6 hours to
obtain azoxystrobin,
d) removing the solvent from the mixture of step (c) by distillation under
reduced
pressure; and further washing and extracting the reaction mixture with a non-
polar organic solvent, non-limiting examples being toluene, xylene, at least
C4
acetate esters, preferably, butylacetate and adding water to obtain an organic
and aqueous phase, thereafter discarding the aqueous phase and crystallizing
the azoxystrobin from the organic phase by cooling the organic solvent,
filtering the precipitated solid and rinsing thereafter with an alcohol,
preferably methanol to obtain azoxystrobin with purity of 98%-99%.
In yet a further specific embodiment of the present invention azoxystrobin is
prepared
according to the following process:
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a) reacting 2-cyanophenol with sodium hydroxide in DMAA and DMSO, more
preferably DMAA, at a temperature between 60 C to 80 C for about 1 hour,
while removing the water which is formed during the reaction via distillation
with the solvent under reduced pressure of about 20-30mbar, wherein the
mole ratio between 2-cyanophenol and sodium hydroxide is between 1:1 and
1:1.5;
b) adding the aromatic substrate which is (E)-Methyl 2-[2-(6-chlorpyridimin-4-
yloxy)phenyl]-3-methoxypropenoate (Compound of formula (I) to the reaction
mixture obtained in step (a), wherein Compound (I) is added to the reaction
mixture as a solution in DMAA.
NN I
Cl I
Me
OOMe
(I)
c) heating the reaction mixture of step (b) to a temperature in the range of
90 C
to 100 C for 4 to 6 hours to obtain azoxystrobin,
d) removing the solvent from the mixture of step (c) by distillation under
reduced
pressure; and further washing and extracting the reaction mixture with
butylacetate and adding water to obtain an organic and aqueous phase,
thereafter discarding the aqueous phase and crystallizing the azoxystrobin
from the organic phase by cooling the organic solvent, filtering the
precipitated solid and rinsing thereafter with methanol to obtain azoxystrobin
with purity of 98%-99%.
The process for obtaining azoxystrobin according to the present invention
provided
azoxystrobin with purity of 98%-99% and a yield of above 90%. This is a
significant
improvement in comparison to the prior art methods which describe a process
with a
yield of 64%. Furthermore, no tars were detected in the reaction mixture of
the present
invention unlike the prior art method which generates tars which affect the
purity of the
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final product. Hence the process of the present invention is more economical,
produces
less by-products and impurities and further generates considerably less
effluents as a
result of the improved yield. Accordingly, the work up according to the
present process
thus the process also provides improvements in terms of environmental and
working
safety.
Examples
Example I: Preparation of azozystrobin
Dimethylacetamide (DMAA, 400m1), 2-Cyanophenol (0.2M, 28g) and NaOH
(0.225M, 9g) were placed at ambient temperature into the three-necked 1L flask
equipped
with stirrer, condenser and thermometer. Half the amount of DMAA containing
water
traces was distilled at vacuum 20mbar/60-65 C and the mixture was kept at
vacuum
20mbar/ room temperature for lh. The same amount of prime DMAA was added and
Compound (I) (0.2M, 64g) was fed into the flask.
The reaction mixture was heated to 100 C and kept at these conditions for 5
hours (monitored by HPLC - conversion of Compound (I) to Azoxystrobin 98-99%).
DMAA was distilled at vacuum 20mbar/65-70 C. At the end of the distillation
the
temperature can be increased up to 90-100 C.
400g Butylacetate (BuAc) and 200g water were added to the reaction mixture at
50-60 C, the temperature was increased to 80 C and stirred 10-15min. The water
phase
was separated at 80 C to remove DMAA traces and inorganic salts.
For crystallization the BuAc phase was slowly cooled from 80 C to -5 C.
Filtration was done using filter #2. The cake was washed with 60 ml cooled
Butylacetate
or methanol and further dried in oven at 80 C during 15 hours. Azoxystrobin
with purity
98-99% and a yield of 90-92% was obtained.
While embodiments of the invention have been described by way of illustration,
it will be
apparent that the invention may be carried out with many modifications,
variations and
adaptations,-without departing from its spirit or exceeding the scope of the
claims.
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